The expression of the immunogloublin (Ig) genes is determined first by the rearrangement in somatic cells of the genes encoding the variable and constant regions and second, by tissue specific factors which interact with DNA regulatory segments within the Ig genes. We have previously established a system for selecting mutant hybridoma cell lines which express the Ig genes at a reduced level and thus have the potential of precisely identifying the DNA segments which are necessary for normal Ig expression. More recently we have succeeded in developing methods which can detect homologous recombination between transferred and chromosomal Ig genes. This technology offers the possibility of mapping and identifying the Ig gene mutations by a form of marker rescue test. Compared to the gene transfer tests which are currently used to analyze genetic regulatory elements, a method based on homologous recombination would be a vast improvement, both in terms of the savings in time and labor, and in terms of its capacity to map mutations for which the usual gene transfer tests cannot detect a phenotype. This application requests funds first to develop our homologous recombination system as a mapping tool and than to apply this technology to the molecular analysis of regulatory mutations which impair transcription of the Ig mu heavy chain gene.